The pathogenesis of ALI/ARDS involves both procoagulant and inflammatory mechanisms. Extravascular fibrin deposition in the lung is a characteristic pathologic feature of ALI/ARDS and intra-alveolar thrombi develop in the lungs of patients with ALI/ARDS. Tissue factor (TF), the trigger protein for activation of the extrinsic coagulation pathway, has a direct role in promoting these effects as indicated by the elevated levels of TF observed in plasma of ALI/ARDS patients compared to control patients with hydrostatic pulmonary edema. These higher plasma TF levels correlated with increased mortality, fewer ventilator-free days, the presence of disseminated intravascular coagulation and the progression to sepsis in patients with ALI/ARDS, suggesting that systemic activation of coagulation may be clinically important in ALI/ARDS. Additionally, TF levels in pulmonary edema fluid from patients with ALI/ARDS were significantly higher than in control patients. In fact, pulmonary TF levels in patients with ALI/ARDS were found to be approximately 100-fold higher than corresponding plasma levels, suggesting an intra-alveolar source of TF. As a result, we have been interested in developing TF antagonists as a therapeutic strategy for treating ALI/ARDS and other inflammatory disorders. In an experimental E. coli sepsis-induced ALI model in non-human primates, we have shown that an anti-TF monoclonal antibody, ALT-836, could attenuate sepsis-induced abnormalities in gas exchange, pulmonary hypertension, and loss of pulmonary system compliance. The results from our pre-clinical studies prompted us to conduct a single-bolus, dose-escalating, Phase 1/2a trial followed by a 120-patient, 1:1 randomized, placebo-controlled Phase 2 clinical trial (with the option to adjust the dosing regimen after an interim analysis of the first 60 enrolled ALI/ARDS patients). The results of the 18-patient Phase 1/2a trial and first 60 patients of the Phase 2 trial indicated that ALT-836 exhibits favorable pharmacokinetic and pharmacodynamic profiles and is well tolerated at the dose level of 0.06 mg/kg as a single bonus infusion. Analysis of the Phase 2 interim data also suggests that single-dose ALT-836 treatment provides beneficial effects to patients during the first one-two weeks of the treatment period. Thus, an independent study is warranted to examine whether the clinical and biological effects observed with single dose regimen could be extended with multiple doses. Under this SBIR Phase II Competing Renewal proposal, we intend to conduct a 90-patient, 1:1 randomized, placebo-controlled Phase 2 clinical trial to examine the safety, pharmacokinetics and efficacy of multi-dose administration of ALT-836 at the 0.06 mg/kg dose level in patients with sepsis-induced ALI/ARDS. Altor also has an in-licensing agreement in place with Genentech for this product and anticipates that positive clinical results from the proposed study will prompt Genentech to sponsor a large Phase 3 registration trial for regulatory approval of ALT-836 by the US FDA. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to evaluate the clinical utility of a novel anti-tissue factor monoclonal antibody, ALT-836, for treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in a 90-patient, randomized, placebo-controlled, double-blind, multi-center Phase 2 clinical study using a multi-dose regimen. If this trial successfully achieves its clinical efficacy endpoints, ALT-836 will then be tested in a pivotal Phase 3 registration trial needed for regulatory approval in order to become the first effective pharmaceutical treatment approved for ALI/ARDS and address this large unmet medical need.